Nitro-Imidazole Hypoxia Imaging Agents

Abstract

The present invention relates to novel radioactively labeled bioreducible tracers of Formula I useful for detecting hypoxic tumors or ischemic tissue in vivo. In one embodiment, the tracers consist of a 2-nitroimidazole moiety, a triazole, metabolically stable linker with pharmacokinetics enhancing substituents, and a radioisotope. The preferred in vivo imaging modality is positron emission tomography.

Description

FIELD OF THE INVENTION[0001]The present invention relates to novel radioactively labeled bioreducible tracers useful for detecting hypoxic cells in vivo. In one aspect, the present application relates to a novel hypoxia imaging agent that displays low background uptake leading to good tumor to background ratios.BACKGROUND OF THE INVENTION[0002]Positron Emission Tomography (PET) is a molecular imaging technology that is used effectively for the detection of disease. PET imaging systems create images based on the distribution of positron-emitting isotopes in the tissue of a patient. The isotopes are typically administered to a patient by injection of probe molecules that comprise a positron-emitting isotope, such as F-18, C-11, N-13 or O-15, covalently attached to a molecule that is readily metabolized or localized in cells (e.g., glucose) or that chemically binds to receptor sites within cells. In some cases, the isotope is administered to the patient as an ionic solution or by inhal...

AI Technical Summary

Benefits of technology

[0017]The present invention relates to novel radioactively labeled bioreducible tracers useful for detecting hypoxic tumors in vivo. In one embodiment, the tracers consist of a 2-nitroimidazole moiety, a triazole, metabolically stable linker with pharmacokinetics enhancing substituents, and a radioisotope suitable for single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. The preferred in vivo imaging modality is positron emission tomography. Because hypoxic cells resist cytotoxic and radiation therapies, and also possess an increased propensity of proliferation and propagation into nearby tissues, accurate assessment of the hypoxic nature of a patient's cancer can guide and greatly affect the therapeutic regimen and outcome.

Problems solved by technology

Although useful in many contexts, limitations of FDG-PET imaging for monitoring cancer exist as well.

Accumulation in inflammatory tissue limits the specificity of FDG-PET.

Conversely, nonspecific FDG uptake may also limit the sensitivity of PET for tumor response prediction.

Further, physiologically high normal background activity (e.g. in the brain) can render the quantification of cancer-related FDG-uptake impossible in some areas of the body.

Despite the clear clinical value of incorporating PET imaging into patient management, limitations do exist.

In certain instances, current imaging probes lack specificity or have inadequate signal to background characteristics.

While standard chemotherapeutic or radiation regimens are employed to treat a variety of tumors, certain tumor types resist standard therapeutic regimens and thus may worsen a patient's clinical outcome.

For instance, because of the rapid and disorganized growth of cancerous tumors, they oftentimes develop disorganized neovascularization leading to poorly vascularized environments.

Hypoxic tumors are clinically problematic: they resist both the effects of radiation and cytotoxic therapy which can result in treatment failure.

Determining tumor hypoxia via electrode measurements of pO2 concentrations within the tumor is an impractical endeavor at best.

In addition, it is only possible to interrogate superficial tumors with this technique.

[18F]F-MISO successfully identifies hypoxic tumors in patients, however, its slow diffusion into hypoxic tumors requires longer uptake times before imaging and, in addition, high background uptake leads to small tumor to background ratios.

While these hypoxic imaging agents show clinical promise, there exists an unmet need for hypoxia tracers that possess enhanced pharmacokinetic profiles leading to peak signal to noise ratios in shorter periods for faster and potentially more accurate hypoxia assessments.

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